This is a resubmission of a NIDA K08 Mentored Clinical Scientist Award. My career objective is to establish myself as independent investigator with a strong program of preclinical research focusing on the neurobiology of nicotine dependence and major depression. The application proposes a comprehensive, five-year program of supervised training and research with Raymond Niaura, Ph.D., and Lawrence H. Price, M.D., at Brown Medical School, and Marina Picciotto, Ph.D., and Tony P. George, M.D. at Yale School of Medicine. This multidisciplinary team will provide close guidance in a training plan comprised of structured didactics, seminars, and coursework in the Brown Brain Sciences Program and in the Department of Neuroscience at Yale University. The focus of the Research Plan is to characterize the neurobehavioral mechanisms that regulate cigarette cravings and smoking behavior among nicotine dependent individuals with and without vulnerability to major depression. In two double-blind, placebo-controlled challenge studies, acute tryptophan depletion (ATD) and alpha-methyl-para-tyrosine (AMPT) will be used to examine the effects of serotonin and dopamine depletion, respectively, on cravings and smoking topography. The specific aims are: (1) To examine the role of serotonin and dopamine in regulating cigarette cravings and smoking topography in depression vulnerable smokers; (2) To determine the relative effects of ATD and AMPT administration on individual differences in (obsessive craving, reward craving) and smoking topography; (3) To determine whether any changes in cue-induced cravings in response to ATD or AMPT administration correspond to changes in smoking topography; and (4) To explore whether associations among craving-related measures (e.g., obsessive and reward craving), smoking (e.g., topography, blood nicotine levels), and diagnostic group are mediated by changes in mood. Results of this research will increase understanding of the associations among serotonin and dopamine function, cue-induced cravings and vulnerability to major depression, and may have implications for tailoring pharmacological treatments to nicotine craving profiles.